Pre-filled drug-delivery device and method of manufacture and assembly of same

ABSTRACT

A drug delivery device having a base member defining a skin-contacting surface, a syringe serving as a reservoir for the drug, and means for expelling drug from the syringe. The syringe is connected to the base member such that the longitudinal axis of the syringe is substantially parallel to the skin surface. A delivery needle is in communication with the syringe. The needle has an angled bend which directs the tip of the needle substantially perpendicular to the skin-contacting surface. In use, the tip of the needle is adapted to penetrate the skin of the subject.

This application is a Continuation application of, and claims priorityunder 35 U.S.C. §120 to, application Ser. No. 09/103,716 (now U.S. Pat.No. 6,500,150), filed on Jun. 23, 1998 which in turn claims priorityunder 35 U.S.C. §119 (e) of provisional patent A.S.No. 60/093,062 havinga filing date of Jun. 24, 1997 which in turn was converted from utilityapplication Ser. No. 08/881,542 filed on Jun. 24, 1997 which in turnclaimed priority under 35 U.S.C. §119(a)-(d) of Irish Patent ApplicationNo. 970445 filed on Jun. 16, 1997.

TECHNICAL FIELD

This invention relates to pre-filled drug delivery devices, and inparticular to devices for attachment to the skin of a subject having aneedle for penetration of the skin of the subject.

BACKGROUND OF THE INVENTION

WO 97/21457, which is incorporated herein by reference, discloses aliquid drug delivery device having a base member defining askin-contacting surface for application to the skin of a subject. Acolumnar cartridge serving as a reservoir for the drug is connected tothe base member such that in use the longitudinal axis of the cartridgeis disposed substantially parallel to the skin-contacting surface. Adelivery needle communicates in use with the interior of the cartridgeand is adapted to penetrate the skin of the subject, and there isprovided means for expelling a drug out of the interior of the cartridgeand through the skin of the subject via the delivery needle.

It has been found that adapting conventional cartridges (such ascartridges for pen-type insulin injectors, or other drug cartridges wellknown in the art) so as to enable an expelling means to expel the drugtherefrom, and so as to enable communication with a delivery needleforming part of such a device, increases the costs of the cartridgeconsiderably, and this in turn adds to the cost of the overall deviceand hence its attractiveness to consumers. The main reason for this isthat conventional drug cartridges are relatively inexpensive, butredesigning such a component and changing the manufacturing process, orindividually modifying such components drives costs up considerably.

Nevertheless, in technical terms, the devices of WO 97/21457 haveundoubted advantages over the prior art due to the fact that thedisposition of the cartridge parallel to the skin enables the device tobe applied to the skin and worn unobtrusively during drug delivery. Bothapplication of the device and delivery of the drug can be accomplishedin a single step requiring little or no manual dexterity.

A further problem associated with the devices of WO 97/21457 is inrelation to the delivery needle which effectively extends at rightangles to the axis of the cartridge. This may be accomplished by using aconduit arrangement leading from the cartridge to a conventional needle,or by means of a right-angled needle which extends from an end of thecartridge co-axially with the axis of the cartridge and then bendsthrough a right angle to penetrate the skin. The latter arrangement ispreferred since it reduces the number of parts and the complexity of thedevice. However, it may prove difficult to bend a needle whilemaintaining sterility (which is of course essential), since thesterility of the needle is assured by a protective sheath which extendsthe entire length of the needle and which may be damaged in the bendingprocess.

For devices which employ a needle to penetrate the skin there is adanger that after use the device may accidentally infect the patient orothers if not properly disposed of. Our WO 95/13838 discloses anintradermal device of this type having a displaceable cover which ismoved between a first position in which the needle is retracted beforeuse and a second position in which the needle is exposed during use.Removal of the device from the skin causes the cover to return to thefirst position in which the needle is again retracted before disposal.

The present invention aims to decrease the possibilities that the needlecould become exposed by accident before or after use for example by achild playing with the device if not properly disposed of. Clearly giventhe risks associated with infectious diseases, particularly thosecarried by blood, any possibility of accidental infection must beminimised to the utmost and preferably eliminated entirely. Some of thefeatures of devices according to the invention which address theseproblems are set out below, and further advantages will become apparentfrom the following description.

In devices of the present invention, a conventional syringe barrel ismounted relative to a base member defining a skin-contacting surface,with the longitudinal axis of the needle substantially parallel to theskin-contacting surface in use.

SUMMARY OF THE INVENTION

The invention provides a base member defining a skin-contacting surfacefor application to the skin of a subject;

a syringe serving as a reservoir for the drug and which is connected tothe base member such that in use the longitudinal axis of the syringe isdisposed substantially parallel to the skin-contacting surface;

a delivery needle in communication with the syringe, the needle havingan angled bend which directs the tip of the needle substantiallyperpendicular to the skin-contacting surface such that in use the tip ofthe needle is adapted to penetrate the skin of the subject; and

means for expelling a drug out of the interior of the syringe.

Preferably, the syringe is a pre-filled syringe.

By employing a conventional syringe, preferably a pre-filled syringe,the devices of the present invention avoid the need for custom-designedcomponents for which it may be difficult to obtain regulatory approvaland manufacturing validation from bodies such as the U.S. Food and DrugAdministration (F.D.A.) and similar other national bodies.

It has been found that while conventional drug-containing componentssuch as cartridges and pre-filled syringes are relatively inexpensive,redesigning such components and changing the manufacturing process, orindividually modifying such components drives costs up considerably forthe device as a whole, which decreases the attractiveness of suchdevices to customers. Thus, devices of the present invention whichemploy widely available syringe bodies will be advantageous overcorresponding devices which include a non-standard drug chamber.

Preferably, a mounting member is mounted along the length of theexterior of the needle at the angled portion. Such a mounting memberserves two purposes: firstly it acts as a mounting point for a seal orsheath to ensure sterility of the portion of the needle which willcontact or penetrate the skin, and secondly it may assist in the correctbending of the needle during the manufacturing process.

Preferably, the mounting member is permanently affixed to the needle.

Further, preferably, a sealing sheath is mounted on the mounting member.

The sheath is preferably removably mounted on the mounting member.

Preferably, means are provided for driving a piston along the interiorof the syringe barrel, and these means are also mounted relative to theskin-contacting surface. Preferably, both the syringe barrel and thedriving means are mounted within a housing.

In preferred embodiments, the driving means is disposed alongside thesyringe barrel rather than at the end thereof, as this arrangement maylead to a more ergonomic design, as well as to advantages in the mannerin which the driving means may be actuated as will be explained below ingreater detail.

Preferably, the driving means is a gas generator.

Suitably, a tube provides communication between the gas generator and apiston-in the syringe.

In one embodiment, the needle extends from the neck of the syringebarrel parallel to the longitudinal axis of the syringe and then bendsto a substantially right angle, such that the tip of the needle pointsperpendicularly to the longitudinal axis of the syringe.

Preferably, the sealing sheath is provided with a flexible pull tabwhich extends through a release liner.

Further, preferably, when the pull tab is pulled away from the basemember, the release liner is pulled away from a lower surface of thebase member and the sealing sheath is detached from the mounting memberto reveal the needle tip.

In one embodiment, the base member is pivotally mounted to a housing ofthe device.

Preferably, the device is provided with a removable locking member suchas a semi-rigid safety tab which prevents relative movement of the basemember towards the housing following removal of the sealing sheath andthe release liner, thereby retaining the needle within the housing untilskin penetration is required.

Further, preferably, relative motion of the housing towards the basemember causes activation of the gas generator while optionallysimultaneously causing the needle tip to penetrate the skin.

Preferably, the base member is displaceable relative to the housingbetween a first position in which the needle is concealed from theexterior of the device and a second position in which the deliveryneedle protrudes from the device for penetration of the skin, the devicefurther comprising means for locking the device in the first positionafter a single reciprocation of the device from the first position tothe second position and back to the first position.

In this embodiment preferably the locking means comprises a mechanicallatch which is brought into operation by said reciprocation.

In an especially preferred embodiment said latch comprises a pair ofelements mounted on the base member and the housing respectively, saidelements being shaped such that they can have two relativeconfigurations when the base member is in said first position relativeto the housing, namely a movable configuration in which the elements aremutually movable, and a locked configuration in which the elements areprevented from mutual movement, and wherein reciprocation of the basemember and the housing causes the elements to pass from the firstmovable configuration, through an intermediate configuration when thebase member is in said second position relative to the housing, and thento said locked configuration, thereby preventing any further movement ofthe base member relative to the housing.

Also preferably one of said elements is provided with a recess which isadapted to receive a projection on the other of said elements, therecess and the projection being spaced apart from one another in themovable configuration, and being in engagement with one another in thelocked configuration.

Further, preferably, movement of the base member relative to the housingis initially prevented by said removable locking member.

Still further, preferably, the presence of said removable locking memberalso prevents the means for providing a gas from being actuated.

The removable locking member preferably comprises a laminar memberinserted between said base member and said housing.

In a preferred embodiment following delivery of drug through the needle,any residual gas is vented through a release valve.

In one embodiment means are provided for enabling a user to determinethat delivery of drug has been completed.

In a further embodiment, the syringe barrel is provided with an endpiston in addition to an internal piston so as to allow for mixing of adrug in a lyophilised form with a diluent, said internal pistoninitially dividing the interior of the syringe barrel into a diluentcompartment and a drug compartment.

Preferably, the pressure resulting from the gas generator is transmittedthrough the diluent compartment so as to push the internal piston intothe drug compartment allowing for ingress of diluent into said drugcompartment.

In a further preferred embodiment a travel limiting mechanism isprovided to limit the maximum amount of travel of the internal pistonalong the length of the syringe barrel so that the dose of drug can beadjusted to suit individual user needs.

It will be appreciated that the locking means described herein iscapable of having a broad application in drug delivery devices having adrug delivery needle.

Thus in a further embodiment the invention provides a drug deliverydevice comprising:

a housing having an internal drug reservoir;

a drug delivery needle extending from the housing for penetration of theskin of a subject, the needle having an outlet for drug delivery;

a base member defining a skin-contacting surface for application to theskin of a subject, said base member being displaceable relative to thehousing between a first position in which the needle is concealed fromthe exterior of the device and a second position in which the deliveryneedle protrudes from the device for penetration of the skin, the devicefurther comprising means for locking the device in the first positionafter a single reciprocation of the device from the first position tothe second position and back to the first position.

Preferably, the base member is pivotally mounted to the housing.

Preferably, the locking means comprises a mechanical latch which isbrought into operation by said reciprocation.

Also preferably, said latch comprises a pair of elements mounted on thebase member and the housing respectively, said elements being shapedsuch that they can have two relative configurations when the base memberis in said first position relative to the housing, namely a movableconfiguration in which the elements are mutually movable, and a lockedconfiguration in which the elements are prevented from mutual movement,and wherein reciprocation of the base member and the housing causes theelements to pass from the first movable configuration, through anintermediate configuration when the base member is in said secondposition relative to the housing, and then to said locked configuration,thereby preventing any further movement of the base member relative tothe housing.

Further, preferably, one of said elements is provided with a recesswhich is adapted to receive a projection on the other of said elements,the recess and the projection being spaced apart from one another in themovable configuration, and being in engagement with one another in thelocked configuration.

Still further, preferably, movement of the base member relative to thehousing is initially prevented by said removable locking member.

The invention also includes a method of manufacturing and filling drugdelivery devices in which a syringe barrel is filled with a drug understerile conditions, with the fluid path and the skin-contacting andpenetrating portion of the needle also sealed or sheathed under sterileconditions. After this is completed, the remainder of the manufacturingand assembly steps can be carried out in a clean area (as opposed to asterile area) since the sealed pre-filled syringe barrel remainssterile.

Thus, the invention provides a method for manufacturing and filling adrug delivery device comprising:

providing a base member having a skin-contacting surface; a syringehaving drug therein and which is connected to the base member such thatin use the longitudinal axis of the syringe is disposed substantiallyparallel to the skin-contacting surface; a delivery needle incommunication with the syringe, the needle having an angled bend whichdirects the tip of the needle substantially perpendicular to theskin-contacting surface such that in use the tip of the needle isadapted to penetrate the skin of the subject; and means for expelling adrug out of the interior of the syringe, filling the syringe barrel withthe drug under sterile conditions with the drug delivery path and theskin-contacting and skin-penetrating portions of the needle understerile conditions and carrying out the remainder of the manufacturingand assembly steps in a clean area.

The term “clean area” denotes an area of high cleanliness as would beexpected for manufacturing medical devices. The term “sterile area”denotes a higher standard of cleanliness (i.e. sterility) such as isrequired for areas in which syringes are pre-filled. While medicaldevices must be assembled in clean areas according to well definedstandards, the level of cleanliness is not as stringent as for a fillingsuite in which parenteral drug containers are filled. By pre-filling andsealing all parts of the fluid path, one obtains a component which canbe assembled with other components under normal clean area conditions.

Preferably, the sterility of the drug delivery path and theskin-contacting and skin-penetrating portions of the needle is achievedby securely affixing a mounting member along the exterior length of theneedle under sterile conditions.

Further, preferably, the drug delivery path and the skin-contacting andskin-penetrating portions of the needle are sealed by means of a sheathmounted on the mounting member.

Preferably, the external mounting member is used as a bending point whena right-angled needle is required.

The sterility of portion of the needle adjacent the needle tip may beassured by securely affixing a mounting member along the exterior lengthof the needle and ensuring that the mounting member and needle aresterile, following which a sheath or seal is mounted on the mountingmember. Subsequent steps of manufacture can then be carried out on theneedle without compromising sterility. For example, the externalmounting member can be used as a bending point if a right-angled needleis required.

Because of the difficulties in manipulating axially unsymmetriccomponents on a mass-production line, particularly where an unsymmetricpart of the component protrudes sideways from an otherwise regulardevice (e.g. a syringe barrel with a bent needle extendingperpendicularly for skin penetration) it is desirable to bend the needleas late as possible in the assembly process.

Conversely, because the sheath guarantees sterility, it is desirable tosheath the needle as early as possible in the manufacturing process(since remaining steps can be carried out in the less expensive cleanarea).

However, when a seal or sheath is mounted on the neck of the barrel tocover the needle, it is difficult to bend the needle without damagingthe sheath and compromising sterility. Equally, it is difficult to mounta sheath on a bent needle since the manipulation may be difficult andthe tip of the needle is likely to damage the sheath. Thus, the use of asterile sheath and the requirement of a bent needle give rise to aconflict as to the most desirable method of manufacture.

The use of a mounting member solves this problem in two respects.Firstly, it enables the sheath to be applied at an early stage (duringthe filling of the syringe barrel, for example). The sterile barrel canthen be removed from the sterile area for further manufacturing/assemblysteps. Secondly, the needle can be bent with the sheath intact withouthaving to contact the sheath and risk damage. The needle can be held bythe mounting point and bent, and this step can be carried out in a cleanenvironment without any risk to the sterility of the fluid path or theportion of the needle which penetrates or contacts the skin.

In a further aspect the invention provides a method of delivering drugto a subject comprising the steps of:

providing a drug delivery device having a skin-contacting surface, asyringe having drug therein, and which is connected to the base membersuch that in use the longitudinal axis of the syringe is disposedsubstantially parallel to the skin contacting surface, a delivery needlein communication with the syringe, the needle having an angled bend, andmeans for expelling a drug out of the interior of the syringe;

applying the device to the skin of the subject; and

activating the device.

Preferably, the tip of the delivery needle is substantiallyperpendicular to the skin contacting surface such that in use the tip ofthe needle is adapted to penetrate the skin of the subject.

Also preferably, the the means for expelling the drug comprises a gasgenerator.

Further, preferably, the syringe is prefilled.

Also preferably the device is activated by moving the housing towardsthe base member.

Preferably, the movement of the housing simultaneously causes the needleto penetrate the skin.

Further, preferably, the method comprises the step of causing the deviceto lock into position after use whereby the needle tip is recessedwithin the housing.

Other objects, features and advantages of the present invention willbecome apparent upon reading the following detailed description of theembodiments of the invention, when taken in conjunction with thedrawings and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be further illustrated by the following descriptionof embodiments thereof, given by way of example only with reference tothe accompanying drawings.

FIG. 1 is a sectional plan view of a drug delivery device according tothe invention;

FIG. 2 is a sectional side view of the device of FIG. 1, shown afterassembly;

FIGS. 3-5 are sectional side views of the device of FIG. 1, shown insuccessive stages of preparation and deployment for application to theskin of a subject;

FIGS. 6 and 7 are sectional side views of the device of FIG. 1, shownduring and at the end of delivery, respectively;

FIGS. 8 and 9 are plan views of the device of FIG. 1, shown during andat the end of delivery, respectively;

FIG. 10 is a sectional side view of the device of FIG. 1, shown afterthe device has been removed from the skin;

FIGS. 11-13 are sectional side views of the device of FIG. 1 takenthrough the gas generator, at successive stages corresponding to FIGS.4,5 and 10, respectively;

FIGS. 14-18 are sectional side views components of the device of FIG. 1,shown during successive stages of manufacture;

FIG. 19 is a cross-sectional side view of the device of FIG. 1, takenthrough the needle thereof;

FIGS. 20-22 are sectional side views of an alternative embodiment of adevice according to the invention, which enables a lyophilised drug tobe reconstituted and delivered to a subject;

FIG. 23 is a sectional side view of a further variation on the device ofFIG. 1; and

FIG. 24 is a sectional plan view of the device of FIG. 23.

DETAILED DESCRIPTION OF THE INVENTION

In FIG. 1 there is indicated, generally at 10, a drug delivery deviceaccording to the invention. The device 10 comprises a housing 11 inwhich a standard hypodermic syringe barrel 12 is mounted. A drug 13 iscontained in the syringe barrel 12 and the drug is sealed by aconventional syringe piston 14.

A gas generator 15 which will be described in greater detail below ismounted in the housing alongside syringe barrel 12, and a tube 16provides communication between gas generator 15 and piston 14.

A needle 17 is mounted in conventional manner at the neck 18 of syringebarrel 12 to provide a conduit for delivery of drug 13 from syringebarrel 12 under an applied pressure from piston 14.

Referring to FIG. 2, the device 10 can be seen in sectional elevationwith housing 11, syringe barrel 12, drug 13, piston 14, tube 16 andneedle 17 visible. It will be seen that needle 17 extends from neck 18of syringe barrel 12 parallel to the longitudinal axis of syringe barrel12, and that needle 17 then bends through a right angle such that thetip 19 points perpendicularly to the longitudinal axis of syringe barrel12. A plastics mounting member 20 is permanently affixed to needle 17,and a protective sealing sheath 21 is removably mounted on mountingmember 20. Protective sealing sheath maintains the sterility of needle17 below mounting member 20, and in particular needle tip 19.

Housing 11 has a base member 22 pivotally mounted thereon at a hinge 23.The lower surface 24 of base member 22 is provided with a contactadhesive layer (not shown) and a release liner 25 covers the lowersurface 24 before use.

Protective sealing sheath 21 is provided with a flexible plastics pulltab 26 which extends through release liner 25. When pull tab 26 ispulled away from base member 22 (FIG. 3), release liner 25 is peeledaway from lower surface 24 and sealing sheath 21 is detached frommounting member 20 to reveal needle tip 19. Needle tip 19 is stillsomewhat concealed from full exposure by base member 22 which is hingedaway from housing 11.

Following the removal of sealing sheath 21 and release liner 25, thelower surface 24 is applied to the skin to which it adheres. Asemi-rigid safety tab 27 prevents relative movement of base member 22towards housing 11 by passing above a first cylindrical post 28 integralwith base member 22 and below a second cylindrical post 29 integral withhousing 11. Although first cylindrical post 28 is adapted to fit insidesecond cylindrical post 29 and thereby allow base member 22 to movetowards housing 11 about hinge 23, safety tab 27 prevents this whenpresent.

FIG. 4 shows device 10 when safety tab 27 has been removed. A snapaction mechanism (not shown) holds the device 10 in the configurationshown in FIG. 4, but downward pressure on the upper surface 30 ofhousing 11 causes the housing 11 to snap towards base member 22 (mountedon the subject's skin) as shown in FIG. 5. This causes needle tip 19 toshoot through an aperture 31 in base member 22 and thus through thesubject's skin (not shown).

As will be further explained below, the relative motion of housing 11towards base member 22 also causes the activation of gas generator 15(not visible in FIGS. 2-5), and thus at the same moment that needle tip19 penetrates the subject's skin, the gas generator 15 begins togenerate gas, thereby increasing the pressure in tube 16 which in turncauses a driving force to be exerted on piston 14 to drive drug 13through needle 17 for delivery to the subject. Such delivery ispreferably subcutaneous, although it could also be intravenous,intramuscular or intradermal (i.e. to a point within the dermis belowthe epidermis), depending on the configuration of the needle and thepositioning of the device on the skin of the subject.

FIGS. 6 and 7 show the device during delivery of the drug and whendelivery has been completed, respectively. Thus, in FIG. 6, piston 14has moved approximately half-way along the length of syringe barrel 12(and delivered a corresponding fraction of the drug 13 to the subject).

In FIG. 7, the piston 14 has reached the end of syringe barrel 12 andcan travel no further. At this point, the gas generator will still begenerating a residual amount of gas, and a release valve 32 is providedto enable the escape of excess gas into the housing (and thus to theatmosphere) as indicated by the arrows in FIG. 7. Release valve 32 is asimple mechanism comprising a cap 33 which seals a vent 34 under normaloperating conditions and which allows gas to escape in the event of apredetermined overpressure within tube 16.

Syringe barrel 12 is formed of a transparent material and a window 35 inupper surface 30 of housing 11 enables the user to see that delivery hasbeen completed. FIGS. 8 and 9 show the upper surface 30 of housing 11before delivery and when delivery is finished, respectively. Thus inFIG. 8, the user can see drug 13 and in FIG. 9, the user can see thatthe piston 14 has reached the end of its travel and thus that device 10should be removed.

FIG. 10 shows the device 10 when it is removed. To remove the device 10the user pulls housing 11 away from the skin. Before the adhesive forcebetween the lower surface 24 and the subject's skin is overcome, thesnap mechanism (which is designed to provide a lesser resistance to thetractive force exerted in pulling the housing from the skin) snaps tocause housing 11 to move away from base member 22, such that when lowersurface 24 is peeled from the skin the needle 17 is already recessed asshown in FIG. 10. This helps avoid accidental injury or infection andmakes the device safer to handle and to dispose of.

The operation of the gas generator 15 will now be described withreference to FIGS. 11-13, each of which is a sectional elevation takenon a line through the device 10 which passes through the centre of thegas generator 15 rather than along the axis of the syringe barrel 12.Thus, with reference to FIG. 1, the elevations of FIGS. 2-7 and 10 aretaken along the longitudinal axis of the syringe barrel 12, whereas theelevations of FIGS. 11-13 are taken along a line which is parallel tothe longitudinal axis of the device itself, passing through the centreof gas generator 15.

FIG. 11 shows device 10 upon removal of the safety tab 27 but before thehousing 11 is snapped towards base member 22 (i.e. at the same moment asis shown in FIG. 4). Gas generator 15 comprises an upper chamber 36filled with citric acid solution 37 and sealed on its underside by afoil membrane 38 before use, and a lower chamber 39 containing aquantity of sodium bicarbonate 40 and means 41 for penetrating the foilmembrane 38 when upper chamber 36 is pushed towards lower chamber 39.

As shown in FIG. 12, when the housing 11 of device 10 is snapped towardsbase member 22 (i.e. at the moment illustrated in FIG. 5), the foilmembrane 38 is penetrated by penetrating means 41. This causes thecitric acid 37 to mix with the sodium bicarbonate 40 to thereby generategas and drive piston 14 (not shown in FIGS. 11-13) as previouslydescribed.

Because the gas generator 15 is situated alongside syringe barrel 12rather than at the end thereof, it is further from the hinge 23 thanwould otherwise be the case. It may be preferred to move the gasgenerator 15 further from the hinge 23 than is shown in the presentembodiment (see FIG. 1). This would mean that the action of pushinghousing 11 towards base member 22 (i.e. pivoting housing 11 and basemember 22 together about hinge 23) is more effective in causing thepenetration of foil membrane 38, since the further the distance a bodyis from the fulcrum of a lever, the greater the linear movement is for agiven angular movement about the fulcrum. For this reason also, theneedle 17 can penetrate the skin with a quick painless action becausethe needle travels in a predominantly vertical fashion which minimisespenetration and thus any pain involved therein. If the needle werecloser to the hinge, it would travel in a more circular pattern creatinga larger pathway upon penetration and consequently cause more pain. Afurther advantage of moving gas generator 15 away from hinge 23 resultsfrom the fact that the citric acid 37 and sodium bicarbonate 40 aremixed to a greater extent (again due to the higher speed at which thefoil membrane 38 is penetrated), and gas generation is thereby smoother.

FIG. 13 shows the device when the housing 11 has been retracted from thebase member 22 and gas generation is completed (equivalent to the viewin FIG. 10).

FIGS. 11-13 also illustrate a tamper-proof safety mechanism whichensures that device 10 is a single use device and that the needle 17cannot be re-deployed after removal from the skin of a subject.

Thus, in FIG. 11 there is shown a sloped surface 42 integral withhousing 11 and a post 43 connected to housing 11 in a resilientlyflexible manner. A generally “F”-shaped member 44 is connected to basemember 22 in a resiliently flexible manner, and a catch 45 adapted toreceive and retain “F”-shaped member 44 is integral with base member 22.

As shown in FIG. 12, when housing 11 is pushed towards base member 22,sloped surface 42 engages “F”-shaped member 44 and pushes a projection46 over catch 45. Projection 46 deflects post 43 at the same time. Whenhousing 11 is pulled away from base member 22 at the end of delivery(FIG. 13), post 43 clears the top of projection 46 (which is held in theFIG. 12 position by catch 45), and post 43 returns to the relaxedposition as in FIG. 11. At this stage, the device is locked and nofurther movement of housing 11 relative to base member 22 is possiblebecause projection 46 prevents any downward movement of post 43. Thus,the needle 17 can only be deployed on a single occasion, i.e. when thedevice is applied to the skin for the first time.

As previously indicated, the invention provides a method of manufacturewhich utilises a standard hypodermic syringe and which allows a sterilesheathed needle to be bent without risk of compromising the sterility. Amethod of manufacturing the device of FIGS. 1-13 will now be describedto illustrate these advantages.

In FIG. 14 the syringe barrel 12 is shown prior to assembly in thedevice according to the invention. Thus, there is shown a standardhypodermic syringe barrel 12 with a standard piston 14 sealing a drug13, and with a needle 17 mounted thereon in conventional manner. Thesyringe barrel is filled with the drug and sealed with the piston in themanner currently used for filling pre-filled syringes. After attachingthe needle 17 to the syringe barrel 12, the mounting member 20 ispermanently attached to the needle and this assembly is sterilised (suchas by steam sterilisation or gamma irradiation), and a protectivesterile sealing sheath 21 is mounted on the mounting member 20.

The assembly shown in FIG. 14 can be safely removed to a clean room forall further manufacturing/assembly steps in the knowledge that theinternal fluid path (i.e. the sealed interior of syringe barrel 12) andthe internal bore of needle 17) is sterile, as is the portion of theneedle from the tip 19 to the mounting member 20. It is important tonote that the needle 17 as shown in FIG. 14 is axially symmetric, i.e.it can be moved around a production line without difficulty (the samewould not necessarily be true if the needle were already bent).

FIG. 15 shows the gas generator 15 and tube 16 (including valve 32)during manufacture. Tube 16 is straight initially which again assists inhandling in a mass production environment.

Outside the sterile area, i.e. in a clean room, the tube 16 is mountedon the syringe barrel 12 (see FIG. 16) and the needle 17 is bent bymanipulating the mounting member 20, i.e. without manipulating sheath21. Mounting member 20 is shaped to ensure a smooth bend.

Referring next to FIG. 17, the assembly of gas generator 15, tube 16 andsyringe barrel 12 is mounted in housing 11 and safety tab 27 is fittedin position. Tube 16 may be completely flexible or it may be permanentlybent into the required curved shape before being fitted to housing 11.

FIG. 18 shows the device when base member 22 is connected to housing 11.Base member 22 is fitted with release liner 25 already in position, sothat it is only necessary to fit pull tab 26 through an apertureprovided in release liner 25 for this purpose. Device 10 is then readyto be packaged, although it may be desired to fold pull tab 26 to lieagainst release liner 25 (as illustrated in FIG. 2).

It can be seen that the design of the device allows the majority of themanufacture and assembly to occur outside a sterile area while stillensuring that those parts of the device for which sterility is requiredremain sterile.

FIG. 19 shows a sectional view through needle 17, mounting member 20,protective sealing sheath 21 and pull tab 26 which illustrates the exactassembly of these components.

FIG. 20 shows a variant on the device already illustrated, in which likenumerals are designated by like reference numerals, the only differencebeing that the syringe barrel 12 is of the type used for drugs which areprovided in lyophilised form and mixed with diluent prior to use. Suchsyringe barrels are known in the art.

The barrel 50 is provided with an end piston 51 which is acted on by gaspressure from a gas generator as previously described. An internalpiston 52 initially divides the interior of syringe barrel 50 into adiluent compartment 53 and a drug compartment 54. The internal bore ofthe syringe barrel 50 is greater in the drug compartment 54 than in thediluent compartment 53. Thus, while internal piston 52 makes a sealedsliding fit with the narrower bore, it becomes loose in the wider boreof the drug compartment. Alternatively, the barrel could be of aconstant diameter with a channel along part of the interior surfaceproviding a pathway for the diluent. A lyophilised drug 55 is providedin the drug compartment together with a quantity of entrapped air.Diluent compartment 53 is entirely filled with liquid diluent 56suitable to reconstitute the drug 55.

When gas generation begins, the pressure acting on end piston 51 istransmitted through the diluent 56 to push internal piston 52 towardsdrug compartment 54. Continued gas generation pushes internal piston 52entirely into drug compartment 54 (FIG. 21) and allows the ingress ofdiluent 56 into drug compartment 54 where the diluent reconstitutes thedrug into solution. Continued pressure on end piston 51 forces thereconstituted drug solution out through the needle 17 to the subject fordelivery as previously described.

Although a certain amount of air is pushed through needle 17 ahead ofthe drug solution, the amount involved will not have any adverse effectif delivery is subcutaneous. The design of the device can also beoptimised to minimise or eliminate air from being delivered. Delivery ofdrug continues until the position shown in FIG. 22 is reached, whereinend piston 51 and internal piston 52 have travelled the maximum distanceand substantially all drug has been delivered.

It should be noted that the barrel 50 and pistons 51,52 are shaped suchthat gas cannot be pumped to the patient after delivery of the drug iscompleted.

FIG. 23 shows a further feature which may be incorporated into devicesaccording to the invention. A travel limiting mechanism is provided tolimit the maximum amount of travel of a piston 14 along the length of asyringe barrel 12. The travel limiting mechanism comprises an adjustablelength of fish line 60 connected at one end 61 thereof to the piston 14and at the other end 62 thereof (FIG. 24) to length adjustment means inthe form of a knurled wheel 63 which can be rotated to shorten orlengthen the line 60. The line can provide from 100% travel down to 70%travel depending on the setting of the wheel 63. The wheel may beadjustable by the patient or it may be designed to prevent patienttampering and to allow only a physician or pharmacist to makeadjustments.

The advantage of this arrangement is that it converts the device of FIG.1 from a single dose device to one in which the dose can be adjusted tosuit individual patients. Many drugs are administered on a “body weightbasis” (e.g. a certain number of milligrams of drug per kilogram bodyweight), and so the dosage must be varied to suit each patient. Byproviding a series of devices with complementary dosages, a manufacturermay be able to cater for a broad selection of patients.

For example in a series of two devices (sizes “A” and “B”), each beingadjustable to deliver from 70% to 100% of the total pre-filled dose,size “A” may contain 100 units (arbitrary units). Thus, device “A” candeliver from 70 to 100 units by adjustment of suitable travel limitingmeans. If device “B” is pre-filled with 70 units, then it can deliverfrom 70% to 100% of this dose, i.e. from 49 to 70 units. Thus, with onlytwo devices, doses from 100 units down to less than 50 units can becatered for, covering a wide range of patients on a mg/kg dosage basis.Adding third or fourth device sizes to the series extends the possibledelivery amounts even further.

It is to be understood that the illustrated travel limiting means areintended only for illustrative purposes and that a wide variety ofequivalent means to control the dosage delivered may be employed.

Furthermore, while the invention has been shown with a simple gasgenerator which delivers the drug at a rate determined by the mixing ofan effervescent couple, the gas generator could also be a moresophisticated, controllable generator, such as an electrolytic cellwhich generates gas at a rate determined by a current which iselectronically controlled.

As used herein, the term, “drug”, is meant to encompass anydrug-containing fluid capable of being passed through a hollow needle ina controlled manner, such as a liquid, solution, gel or fine suspension.The term “drug” used herein includes but is not limited to peptides orproteins (and memetics thereof), antigens, vaccines, hormones,analgesics, anti-migraine agents, anti-coagulant agents, medicationsdirected to the treatment of diseases and conditions of the centralnervous system, narcotic antagonists, immunosuppressants, agents used inthe treatment of AIDS, chelating agents, anti-anginal agents,chemotherapy agents, sedatives, anti-neoplastics, prostaglandins,antidiuretic agents and DNA or DNA/RNA molecules to support genetherapy.

Typical drugs include peptides, proteins or hormones (or any memetic oranalogues of any thereof) such as insulin, calcitonin, calcitonin generegulating protein, atrial natriuretic protein, colony stimulatingfactor, betaseron, erythropoietin (EPO), interferons such as α, β or γinterferon, somatropin, somatotropin, somastostatin, insulin-like growthfactor (somatomedins), luteinizing hormone releasing hormone (LHRH),tissue plasminogen activator (TPA), growth hormone releasing hormone(GHRH), oxytocin, estradiol, growth hormones, leuprolide acetate, factorVIII, interleukins such as interleukin-2, and analogues or antagoniststhereof, such as IL-1ra; analgesics such as fentanyl, sufentanil,butorphanol, buprenorphine, levorphanol, morphine, hydromorphone,hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclofenac,naproxen, paverin, and analogues thereof, anti-migraine agents such assumatriptan, ergot alkaloids, and analogues thereof; anti-coagulantagents such as heparin, hirudin, and analogues thereof; anti-emeticagents such as scopolamine, ondansetron, domperidone, metoclopramide,and analogues thereof; cardiovascular agents, anti-hypertensive agentsand vasodilators such as diltiazem, clonidine, nifedipine, verapamil,isosorbide-5-mononitrate, organic nitrates, agents used in treatment ofheart disorders, and analogues thereof; sedatives such asbenzodiazepines, phenothiazines, and analogues thereof; chelating agentssuch as deferoxamine, and analogues thereof; anti-diuretic agents suchas desmopressin, vasopressin, and analogues thereof; anti-anginal agentssuch as nitroglycerine, and analogues thereof; anti-neoplastics such asfluorouracil, bleomycin, and analogues thereof; prostaglandins andanalogues thereof; and chemotherapy agents such as vincristine, andanalogues thereof, treatments for attention deficit disorder,methylphenidate, fluoxamine, Bisolperol, tactolimuls, sacrolimus andcyclosporin.

It will further be appreciated that many of the embodiments discussedabove are preferred embodiments, falling within the scope of theinvention, and that various alternative embodiments are contemplated.

What is claimed is:
 1. A drug delivery device comprising a base member defining a skin-contacting surface for application to the skin of a subject, a syringe serving as a reservoir for a drug, a delivery needle coupled to said syringe, and means for expelling the drug out of the interior of said syringe and through said needle, said needle having a tip, said syringe having a longitudinal axis and being movably coupled to said base member from a first position to a second position, said longitudinal axis of said syringe when in said first position being at a first angle to said skin contacting surface, said longitudinal axis of said syringe when in said second position being at a second angle to said skin contacting surface, said needle having first portion extending along said longitudinal axis and an angled bend which directs said tip of said needle at an angle to said longitudinal axis, whereupon when said syringe is in said second position said tip of the needle is adapted to penetrate the skin of the subject.
 2. The drug delivery device of claim 1 wherein said second angle is approximately zero degrees, whereupon said longitudinal axis is substantially parallel to said skin contacting surface when said longitudinal axis of said syringe is in said second position.
 3. The drug delivery device of claim 1 wherein said syringe is pre-filled with the drug.
 4. The drug delivery device of claim 1 additionally comprising a mounting member mounted along the length of the exterior of the needle at the angled portion thereof.
 5. The drug delivery device of claim 4, wherein said mounting member is permanently affixed to the needle.
 6. The drug delivery device of claim 5, additionally comprising a sealing sheath mounted on said mounting member.
 7. The drug delivery device of claim 6, wherein said sealing sheath is removably mounted on said mounting member.
 8. The drug delivery device of claim 1 wherein said syringe comprises a barrel and a piston located adjacent said reservoir within said barrel, and wherein said means for expelling the drug out of the interior of the syringe comprises driving means for driving said piston along the interior of said barrel.
 9. The drug delivery device of claim 8, wherein said syringe and said driving means are mounted within a housing.
 10. The drug delivery device of claim 9, additionally comprising a travel limiting mechanism to limit the maximum amount of travel of said piston along the length of said barrel to adjust the amount of the drug provided by the needle to the subject.
 11. The drug delivery device of claim 8, wherein said driving means is disposed alongside said barrel.
 12. The drug delivery device of claim 8, wherein said driving means comprises a gas generator.
 13. The drug delivery device of claim 12, additionally comprising a tube in communication between said gas generator and said piston.
 14. The drug delivery device of claim 12, additionally comprising a housing for said syringe, said base member being movably coupled to said housing, and wherein relative motion of said housing towards said base member causes activation of said gas generator.
 15. The drug delivery device of claim 8, additionally comprising a travel limiting mechanism to limit the maximum amount of travel of said piston along the length of said barrel to adjust the amount of the drug provided by the needle to the subject.
 16. The drug delivery device of claim 1, wherein said tip of said needle extends approximately perpendicularly to said longitudinal axis.
 17. The drug delivery device of claim 16, additionally comprising a flexible pull tab coupled to said sealing sheath.
 18. The drug delivery device of claim 17 additionally comprising a release liner coupled to said skin contacting surface of said base member and to said sealing sheath.
 19. The drug delivery device of claim 18, wherein said pull tab is arranged to be pulled away from said base member, and said release liner is arranged to be pulled away from said skin contacting surface of said base member, whereupon said sealing sheath is detached from said mounting member to expose said needle tip.
 20. The drug delivery device of claim 1, wherein said base member is pivotally mounted with respect to said syringe.
 21. The drug delivery device of claim 20 additionally comprising a housing, and wherein said syringe is located within said housing and said base member is pivotably coupled to said housing.
 22. The drug delivery device of claim 21, additionally comprising a removable locking member which prevents relative movement of said base member towards said housing following removal of said sealing sheath and said release liner, whereupon said needle is retained within said housing until skin penetration is required.
 23. The drug delivery device of claim 22, wherein said removable locking member comprises a semi-rigid safety tab.
 24. The drug delivery device of claim 22, wherein movement of said base member relative to said housing is initially prevented by said removable locking member.
 25. The drug delivery device of claim 24, wherein said means for expelling the drug out of said interior of said syringe comprises gas driving means and wherein the presence of said removable locking member also prevents said gas driving means from being actuated.
 26. The drug delivery device of claim 22, wherein said removable locking member comprises a laminar member inserted between said base member and said housing.
 27. The drug delivery device of claim 22, additionally comprising a travel limiting mechanism to limit the maximum amount of travel of said piston along the length of said barrel to adjust the amount of the drug provided by the needle to the subject.
 28. The drug delivery device of claim 21, wherein relative motion of said housing towards said base member causes said needle tip to penetrate the skin.
 29. The drug delivery device of claim 21, wherein said base member is movable relative to said housing between a first position in which said needle is retracted from the exterior of said device and a second position in which said tip of said needle protrudes from said device for penetration of the skin, said device further comprising means for locking the device in said first position after a single reciprocation of said device from said first position to said second position and back to said first position.
 30. The drug delivery device of claim 29, wherein said locking means comprises a mechanical latch which is brought into operation by said reciprocation.
 31. The drug delivery device of claim 30, wherein said latch comprises a pair of elements mounted on said base member and said housing, respectively, said elements being shaped such that they can have two relative configurations when the base member is in said first position relative to said housing, one of said configurations being a movable configuration in which said elements are mutually movable, and the other of said configurations being a locked configuration in which said elements are prevented from mutual movement, and wherein reciprocation of said base member and said housing with respect to each other causes said elements to pass from said first movable configuration, through an intermediate configuration when said base member is in said second position relative to said housing, and then to said locked configuration, thereby preventing any further movement of said base member relative to said housing.
 32. The drug delivery device of claim 31, wherein one of said elements includes a projection and the other of said elements includes a recess which is adapted to receive said projection elements, said recess and said projection being spaced apart from each other in said movable configuration, and being in engagement with each other in said locked configuration.
 33. The drug delivery device of claim 29, additionally comprising a travel limiting mechanism to limit the maximum amount of travel of said piston along the length of said barrel to adjust the amount of the drug provided by the needle to the subject.
 34. The drug delivery device of claim 1, additionally comprising a release valve, and wherein said means for expelling the drug out of the interior of said syringe comprises gas driving means producing a gas and wherein following delivery of the drug through said needle, any residual gas is vented through said release valve.
 35. The drug delivery device of claim 1, wherein means are provided for enabling a user to determine that delivery of the drug has been completed.
 36. The drug delivery device of claim 1, wherein said syringe comprises a barrel coupled to an end piston and to an internal piston so as to allow for mixing of the drug in a lyophilised form with a diluent, said internal piston initially dividing the interior of said barrel into a diluent compartment and a drug compartment.
 37. The drug delivery device of claim 36, wherein said means for expelling the drug out of said interior of said syringe comprises a gas generator for providing gas under pressure and wherein the gas pressure is transmitted through said diluent compartment so as to push said internal piston into said drug compartment allowing for ingress of the diluent into said drug compartment. 